The present invention relates to measuring endothelial dependent vasoactivity and, more particularly, to a non-invasive method and system for determining endothelial dependent vasoactivity.
Hemodynamics is a subchapter of cardiovascular physiology, which deals with the forces the heart has to develop in order to circulate blood throughout the cardiovascular system. To a physician, these forces are manifested as blood pressure and blood flow paired values measured simultaneously at different points of the cardiovascular system.
The flow of blood through the vasculature has a pulsatile nature. When the heart contracts, part of the blood contained within the left ventricle is squeezed into the aorta from which the blood flows into the entire cardiovascular system. Since blood is an incompressible fluid, when it is squeezed into the vasculature, which exhibits a resistance to blood flow, blood pressure is generated. During ventricular contraction the arterial blood pressure increases to its highest, the systolic level. When the left ventricle is refilled with oxygenated blood from the lungs during the relaxation phase of the cardiac cycle (the diastole), and the ventricle is disconnected from the vasculature by the aortic valve, the pressure in the vasculature decreases to its lowest level.
The amount of blood which is pumped with each heartbeat, also known as the stroke volume, normalized by body surface area is known as the Stroke Index (SI). The mean value of blood pressure is called the Mean Arterial Pressure (MAP). The values of SI and MAP are a result of modulation by several hemodynamic modulators: (i) intravascular volume, (ii) inotropy, (iii) Starling effect and (iv) vasoactivity.
Intravascular volume is the amount of fluid circulating in the vasculature. This modulator can be affected, for example, by dehydration, diuresis, venoconstriction of the spleen, volume overload due to heart or kidney failure and the like.
Inotropy is the ability of the cardiac muscle to contract. Myocytes are the only muscle cells which are able to vary the strength of contraction. Inotropy can be affected by exercise, stress and pharmaceutical agents, which increase the strength of myocardial contractions, or by cardiac diseases such as heart failure, which is expressed by decrease of the strength of contractions. The myocardial contractility is controlled by positive and negative inotropes which instantaneously affect the level of inotropic state. Changes in inotropy alter the rate of force and pressure development by the ventricle.
The heart has the intrinsic capability of increasing its force of contraction when preload is increased. The preload is related to the sarcomere length via the well known Starling law.
Vasoactivity referrers to the ability of blood vessels to expand and contract. Through vasoactivity the body controls the flow of blood through individual organs, accommodate the variation in blood flow and regulate arterial pressure.
The endothelium-dependent relaxation of blood vessels is due to the release of potent non-proslanoid vasodilator substances by the endothelium (the inner most cellular layer of the blood vessel) surrounding the blood vessel. The endothelium-derived relaxing factor is believed to be nitric oxide (NO), which is released by different stimuli substances produced during platelet aggregation. The endothelial action of thrombin and platelet products is crucial for the protective role played by the normal endothelium against unwanted coagulation. Therefore, local platelet aggregation, with the associated release of serotonin and ADP, together with the production of thrombin, leads to a major local release of NO. The NO diffuses towards the underlying vascular smooth muscle, induces its relaxation and thus contributes to the dilatation of the artery. The release of NO to the blood vessel also inhibits platelet adhesion at the endothelium blood interface, exerts a major feedback on platelet aggregation, thereby eliminates the imminent danger of vascular occlusion. In addition, the endothelial barrier prevents the platelet derived vasoconstrictor substances from reaching the smooth muscle. NO can also be released by other stimuli like flow mediated vasoactivity and increased sympathetic activity (alpha receptor stimulation).
It is recognized that dysfunction of endothelial dependent vasoactivity, also known as endothelial dysfunction, is an early event in the pathogenesis of cardiovascular disease. Endothelial dysfunction and coronary artery disease are also linked to over-weight, obesity, hypertension, hypercholesterolemia, hyperlipidemia, diabetes mellitus, cigarette smoking and homocysteine. In addition, the vascular endothelium plays a fundamental role in several processes related to thrombosis. Impaired endothelium function may also promote the development of atherosclerosis through its effects on vaso-regulation, platelet and monocyte adhesion.
Several studies have demonstrated that elevated concentration of total cholesterol and low density lipoprotein cholesterol are associated with impaired endothelial function, independent of the presence of coronary heart disease [Robert A. Vogel, “Coronary risk factors, Endothelial function, and atherosclerosis: A review,” Clin. Cardiol 1997, 20:426-432; Robert A. Vogel et al., “Changes in flow-mediated brachial artery vasoactivity with lowering of desirable cholesterol levels in healthy middle aged men,” The American journal of cardiology 1996, 77; Kensuke Egashira et al., “Reduction in serum cholesterol with pravastatin improves endothelium dependent coronary vasomotion in patients with hypercholesterolemia,” Circulation 1994, 89 No 6]. In addition, decreased concentrations of high-density lipoprotein cholesterol and an elevated ratio of total to high-density lipoprotein cholesterol have also been associated with endothelial dysfunction.
Cigarette smoking profoundly impairs endothelial function [Robert W. stadler et al., “Measurment of the time course of peripheral vasoactivity: results in cigarette smokers,” Atherosclerosis 1998 138:197-205; David S. Celermajer et al., “Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults,” Circulation 1993, 88, No 5 part 1]. Endothelial function is reduced in both active and passive smokers in a dose dependent manner. Smoking cessation is associated with improvement in endothelial function.
Endothelial dysfunction increases in men over the age of about 40 and in women after the age of about 55, whether or not other coronary risk factors are present. The specific cause of the decrease in endothelial function with age is yet unknown. Estrogen appears to be a major factor associated with gender differences in age-related endothelial function.
Other factors which affect endothelial function include hypertension [Perticone F, et al., “Prognostic significance of endothelial dysfunction in hypertensive patients,” Circulation 2001, 104:191-196], diabetes [Cosentino F et al., “Endothelial dysfunction in diabetes mellitus,” J Cardiovasc Pharmacol, 1998, 32:54-61; Cosentino F et al., “High glucose causes upregulation of Cyclooxygenase-2 and alters prostanoid profile in human endothelial cells. Role of protein kinase C and reactive oxygen species,” Circulation 2003, 107:1017-1023], diet and physical exercise [Brendle D et al., “Effects of exercise rehabilitation on endothelial reactivity in older patients with peripheral arterial disease,” Am J Cardiol 2001, 87:324-329].
The full range of different diseases associated with endothelial dysfunction, the nature of endothelial abnormalities and the effects of potential treatments on vasoactivity are yet to be determined. Nevertheless, the measurement of arterial endothelium function is of utmost importance for the purpose of diagnosing endothelial dysfunction related diseases at early stage, for example for diagnostic assessment of atherosclerothic disease in the pre-stenotic stages [Vanhoutte. P. M., “Endothelial dysfunction and atherosclerosis,” Eur Heart J, 1997:18 (sup E) E19-E29; Robert A. Vogel, 1997 ibid; Mary C. Corretti et al., “Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilatation of the brachial Artery,” JACC 2002, 39:257-65; Widlansky M E, Gokee N, Keaney J F Jr, Vita J A, J, “The clinical implications of endothelial dysfunction,” J Am Coll Cardiol 2003, 42:1149-60].
Normal release of NO prevents and/or attenuates arteriosclerosis as well as other major factors such as thrombosis [Robinson Joannides et al., “Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo,” Circ. 1995, 91:1311-12; Ian B. Wilkson et al., “Nitric oxide regulates local arterial distensibility in-vivo,” Circ. 2002, 105:213-217].
Many studies have demonstrated that endothelial dysfunction in coronary arteries is concomitant with impaired endothelial brachial, radial and the carotid dysfunction [Corretti et al., 2002 ibid; Tod J. Anderson et al., “Close relation of endothelial function in the human coronary and peripheral circulations,” JACC 1995, 26:1235-41; David S. Celermajer et al., “Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction,” JACC 1994, 24:1468-74; Sorensen K E et al., “Atherosclerosis in the human brachial artery,” JACC 1997, 29:318-22]. In addition, it was found that coronary artery disease is related to atherosclerothic disease in the aorta and the carotid artery [Khoury Z et al., “Relation of coronary artery disease to atherosclerothic disease in the aorta, carotid, and femoral arteries evaluated by ultrasound,” Am J Cardiol 1997, 80:1429-1433].
Assessment of endothelium dependent vasoreactivity (EDV) in coronary arteries may be performed by measurements of changes in peripheral arterial diameter due to pharmacological or mechanical stimuli.
One method for measuring the inner diameter of a blood vessel is by an intravascular ultrasound device having an intravascular catheter and an ultrasound transducer array mounted thereon. The intravascular catheter is inserted directly into the artery of interest to thereby determine its inner diameter.
Such a device is highly invasive, expensive and requires costly additional technical expertise to operate.
Another known device for measuring the intravascular diameter of a blood vessel has an elongated flexible sheath and a catheter which is longer than the sheath. The sheath has an outer diameter which is less than the intravascular diameter. The catheter proximal end extends outwardly from the proximal end of the sheath and includes a measuring scale directly proportional to a position of a sensor extending from the catheter. When the sheath is inserted into the blood vessel and the catheter is moved inwardly relative to the sheath, the intravascular diameter can be read directly from the measuring scale.
This device, however, although simple and not expensive, is still highly invasive and lacks the necessary accuracy for the purpose of determining vasoactivity.
Also known in the art are non-invasive methods for the measurement of arterial diameter by high resolution non-invasive ultra-sound systems. In one such method the physician operates an ultrasound transducer to obtain appropriate ultrasound images of the brachial artery for measuring artery diameter thereof. This method, however, is time consuming, and requires a highly trained physician or technician to hold the transducer stably during the measurement.
In another such method, an automatic measurement system having a robot arm manipulating ultrasound imaging probe is used. The system automatically navigates the ultrasound imaging probe to an appropriate position and measure changes in diameter of brachial artery with improved reproducibility compared with manual measurement.
This procedure, however, is very costly, requiring highly practiced personnel and equipment, and thereby lacks the ability to become a standard clinical procedure in the assessment of endothelial dysfunction in large high-risk populations.
The autonomic nervous system (ANS) plays a cardinal role in the control of cardiovascular function. Heart rate, heart excitability and contractility are under the constant influence of the parasympathetic-sympathetic balance. Parasympathetic nerves and sympathetic fibers innervate the sino-atrial node; the parasympathetic influence is inhibitory while the sympathetic influence is excitatory. The parasympathetic fibers to the SA node are driven by inhibitory and excitatory inputs from peripheral receptors (baroreceptors, chemoreceptors, cardiac, pulmonary and airway receptors). Behavioral adaptive influence of the heart rate at the sinus node is mediated by supramedullary inputs to the cardiovagal neurons. The origin of the sympathetic innervation of the heart is located at the T2-T5 segment of the spinal cord and the preganglionic fibers synapse in the cervical ganglia.
Normal cardiac function is regulated by the complex balance of the sympathetic and parasympathetic outflows to the heart. This balance is also responsible for the susceptibility to arrhythmias: while vagal activity has a protective role, sympathetic activity lowers the threshold to ventricular fibrillation. Normal heart function, heart rate included, is modulated by the fluctuations in the sympathetic and parasympathetic flow to the heart. These fluctuations induce beat-to-beat variability in heart rate and arterial pressure. Hence, the analysis of the instantaneous fluctuations in cardiovascular variables supplies valuable information on the autonomic control in an intact organism.
Over the past two decades, analysis of electrocardiogram (ECG) signals in general and Heart-Rate-Variability (HRV) in particular, have been used to quantify the behavior of the ANS [Malik et al., “Guidelines. Heart rate Variability,” Eur Heart J 1996, 17:354-381]. It was found that about 5 minutes recording of HRV are sufficient for detecting possible existence of coronary artery disease [Parati et al., “Spectral analysis of blood pressure and heart rate variability in evaluating cardiovascular regulation. A critical appraisal,” Hypertension 1995, 25(6): 1276-86; Hayano J et al., “Decreased magnitude of heart rate spectral components in coronary artery disease and its relation to angiographic severity,” Circulation 1990, 81(4):1217-24].
There is thus a widely recognized need for, and it would be highly advantageous to have, a simple, cost effective, non-invasive method and system for determining endothelial abnormal function.